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Heritable ER stress impairs mitochondrial metabolism and leads to exhaustion of low-dose irradiated hematopoietic stem cells [RREMseqHSC]

ABSTRACT: How hematopoietic stem cells (HSC) respond to low levels of stress such as exposure to very low doses of radiation currently used in medicine, is largely unknown. Here, we show that 20mGy-irradiated HSC (20mGy-HSC) exhibit, when they proliferate, oxidative stress with increased mitochondrial Reactive Oxygen Species and metabolism together with mitochondrial Ca2+ overload. These mitochondrial defects are due to an immediate and sustained endoplasmic reticulum (ER) stress adapted by proliferative 20mGy-HSC through activation of the eIF2-ATF4 branch of the UPR. The ER stress is heritable and leads, in long-term quiescent 20mGy-HSC, to activation of the IRE1-Xbp1 branch of UPR, which fails to restore ER homeostasis resulting in HSC self-renewal deficiency and exhaustion. Finally, we show that this heritable ER stress leads to a global DNA hypomethylation, partially reverted by early inhibition of ER stress. Our studies illuminate how an adaptive ER stress response can lead to mitochondrial defects and HSC deficiency.

ORGANISM(S): Mus musculus

PROVIDER: GSE281655 | GEO | 2026/01/13

REPOSITORIES: GEO

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Project description:Cells rely on the Unfolded Protein Response (UPR) to maintain ER homeostasis (proteostasis) when faced with elevated levels of misfolded and aggregated proteins, which can hinder the secretion of properly folded proteins. The UPR is composed of three main branches—ATF6, IRE1, and PERK—that coordinate the synthesis of proteins involved in folding, trafficking, and degradation of nascent proteins to restore ER function. Dysregulation of the UPR is linked to numerous diseases, including neurodegenerative disorders, cancer, and diabetes. Despite its importance, identifying UPR targets has been challenging due to their heterogeneous induction, which varies by cell type and tissue. Additionally, defining the magnitude and range of UPR-regulated genes is difficult because of intricate temporal regulation, feedback between UPR branches, and extensive cross-talk with other stress-signaling pathways. To comprehensively identify UPR-regulated proteins and determine their branch specificity, we developed a data-independent acquisition (DIA) liquid-chromatography mass spectrometry (LC-MS) pipeline. Our optimized workflow improved protein identifications of low-abundant UPR proteins and leveraged an automated SP3-based protocol on the Biomek i5 liquid handler for label-free peptide preparation. Using engineered stable cell lines that enable selective pharmacological activation of each UPR branch without triggering global UPR activation, we identified branch-specific UPR proteomic targets. These targets were subsequently applied to investigate proteomic changes in multiple BRAF-mutant melanoma cell lines, representing different genetic backgrounds, treated with a BRAF inhibitor (PLX4720, i.e., vemurafenib). Our findings revealed differential regulation of the XBP1s branch of the UPR in the BRAF-mutant melanoma cell lines after PLX4720 treatment, likely due to calcium activation, suggesting that the UPR plays a role as a non-genetic mechanism of drug tolerance in melanoma. In conclusion, the validated branch-specific UPR proteomic targets identified in this study provide a robust framework for investigating this pathway across different cell types, drug treatments, and disease conditions in a high-throughput manner.

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Heritable ER stress impairs mitochondrial metabolism and leads to exhaustion of low-dose irradiated hematopoietic stem cells [RREMseqHSC]

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